The overall aim of this application is to evaluate the ability of antibodies generated against novel HIV-envelope immunogens to protect Rhesus macaques from SHIV-infection, or to delay the onset of disease. The proposed studies are based on our observation that deletion of the V2 loop from the envelope of the primary, CCR5-using HIV-I isolate, SF162, renders the virus, termed SF162 deltaV2, highly susceptible to antibody- mediated neutralization, because it results in the exposure of an envelope region containing neutralization epitopes which are conserved among heterologous primary isolates. We report that immunization of rabbits with the SF162 deltaV2 envelope elicits higher titers of neutralizing antibodies than the unmodified SFI62 envelope. We also report that immunization of Rhesus macaques with the SF162 deltaV2 envelope elicits the generation of potent envelope-specific Tlymphoproliferative responses and antibodies that not only are capable of neutralizing the homologous SF162 deltaV2 and parental SFI62 viruses, but also all the primary heterologous HIV-I isolates tested so far. Our proposed studies will focus on the following: (I) Continue our efforts to identify envelope modifications that expose neutralization epitopes on the HIV envelope; (2) Compare the development, maturation, epitope-specificity and neutralizing potential of antibodies generated in Rhesus macaques by the parental SF162 unmodified envelope and by the various modified envelopes; (3) Compare the ability of the antibodies generated by the modified and unmodified envelopes to protect Rhesus macaques from SHIV-infection; (4) Compare the envelope-specific antibody responses generated in Rhesus macaques infected by SHIV viruses expressing the 5FI62 envelope, to those generated during immunization by our various immunogens.